This invention relates to a method of regulating secretions in and around the mucous membranes of a mammal by administering purinergic receptor agonists such as certain uridine, adenine, or cytidine diphosphates as well as other nucleoside phosphate compounds.
There are many situations where it is therapeutically desirable to increase the amount of hydration on mucosal surfaces of the body. Mucus membranes are hydrated surface epithelial tissues that line cavities exposed to the outside environment. These mucosal surfaces of the body must stay hydrated with the proper mixtures of water, salt, mucin and other proteins in order to defend the body from the outside world and remain comfortable. The mucus membranes play a major role in fighting off infections and keeping the exposed organs clean and healthy. Mucus membranes are found on the surface of the eye, vagina, sinonasal cavities and mouth (oropharyngeal). Impaired hydration of these mucus membranes leads to medical conditions such as: dry eye, vaginal dryness, rhinosinusitis, dry mouth, corneal injury, and others.
Dry eye disease is the general term for indications in which the mucous membranes surrounding the eye are not properly hydrated due to an imbalance of salt, water and mucus in the precorneal tear film. Dry eye is characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease that results. Approximately 38 million Americans are affected with some type of dry eye disorder. Among the indications that are referred to by the general term xe2x80x9cdry eye diseasexe2x80x9d are: keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren""s syndrome, ocular cicatrical pemphigoid, blepharitis, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamin deficiencies), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink. The present invention may also be useful as a wash or irrigation solution in conscious individuals, during surgery or to maintain comatose patients or those who cannot blink due to neuromuscular blockade or loss of the eyelids.
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. However, relief is short-lived and frequent dosing is necessary. In addition, artificial tears often have contra-indications and incompatibility with soft contact lenses (M. Lemp, Cornea 9(1):S48-550 (1990)). The use of phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phosphodiesterase inhibitors is currently being investigated (J. Gilbard, et al., Arch. Ophthal. 112:1614-16 (1994) and 109:672-76 (1991); idem, Inv. Ophthal. Vis. Sci. 31:1381-88 (1990) Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154.
Vaginal dryness is a very common problem which brings physical and emotional distress to many women (E. Key, Nurs. Stand. 5:24-27 (1991)). It most commonly manifests itself during sexual intercourse, which causes dyspareunia and can eventually lead to apareunia. Although it is traditionally considered to be a condition which affects postmenopausal women, it can occur during the premenopausal and perimenopausal years. The use of oral contraceptives may also cause a reduction in vaginal moisture in some women (W. Reginald, et al., Br. J. Obstet. Gynaecol. 96:1148-1152 (1989)). Postpartum vaginal dryness, independent of or as a result of lactation, can be a significant complaint (P. Wisniewski, et al., Am. J. Obstet. Gynecol. 165:1249-1254 (1991)). Women undergoing chemotherapy or radiotherapy for malignant diseases such as leukemia often experience vaginal dryness as a result of treatment (M. Cust, et al., Br. Med. J. 299:1494-1497 (1989)). Many disease states, such as systemic sclerosis and other systemic autoimmune disorders (S. Bhadauria, et al., Am. J. Obstet. Gynecol. 172:580-587 (1995)), Ehlers-Danlos syndrome (Y. Sorokin, et al., J. Reprod Med. 39:281-284 (1994)), diabetes mellitus (L. Sreebny, et al., Diabetes Care 15:900-904 (1992)), and Sjxc3x6gren""s syndrome (D. Marchesoni, et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 63:49-53 (1995)) have decreased vaginal hydration and lubrication problems as significant disease-associated symptoms.
Current therapies for increasing vaginal moisture are: lubricating agents such as lubricating creams or jellies, topical estrogen creams, and HRT (hormone replacement therapy). Lubricating jellies provide short-lived and temporary relief, as these are aqueous preparations containing no pharmacologically active agent. Topical estrogen creams, if used on a regular basis, may be absorbed into the systemic circulation. This can cause endometrial stimulation and can lead to endometrial hyperplasia and carcinoma (M. Whitehead, et al., N. Eng. J. Med. 305:1599-1605 (1981)). HRT is effective at relieving symptoms of vaginal atrophy and hence vaginal dryness but has several contraindications and unwanted risks and side effects.
Another disease state characterized by improper hydration of mucus secretions is acute and chronic sinusitis, or rhinosinusitis as it is currently referred to by otolaryngologists. Rhinosinusitis is a disease of the paranasal sinuses typically associated with retained, thick mucus secretions. It is this country""s most common health-care complaint, affecting an estimated 31 million people (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS) 86-1588 (1985)).
Dry mouth is a condition in which the mucus membranes of the oropharyngeal cavity becomes dehydrated, leading to discomfort, difficulty swallowing and bad breath. Among the conditions generally referred to as xe2x80x9cdry mouthxe2x80x9d are, but not limited to: Sjogren""s syndrome, chemotherapy and post radiation treatment, and pharmacologic side effects.
Thus, as a result of the ineffectiveness and risks of current therapies, medical researchers have sought to develop alternatives for the treatment of dehydrated mucus membranes. Use of UDP and ADP for the purpose of treating pulmonary disorders characterized by the retention of lung mucus secretions is described in Patent Application (Boucher, R. C., Jr., et al., PCT/US98/17894). Applicants were motivated to investigate whether UDP and other P2Y6 receptor agonists could stimulate hydration and mucin production on mucosal surfaces throughout the body, such as in the eye, female reproductive tract, sinonasal and oropharyngeal cavities.
Applicant has discovered that ion, mucin and fluid secretion can be stimulated from mucous membrane tissues via P2Y6 purinergic receptor-mediated mechanisms. UDP and other purinergic receptor agonists, administered topically or systemically, provide a novel method of treating disorders of mucosal hydration.
Applicant has also discovered that UDP and other diphosphate agonists of the P2Y6 receptor also facilitate expectoration of deep lung mucus. Such expectoration is useful in a method of diagnosing lung diseases whereby the expectorated deep lung mucus is analyzed for cytological abnormalities indicative of lung disease, such as lung cancer and tubeculosis.
A method of stimulating mucosal hydration in a subject in need of such treatment is disclosed. The method of the present invention may be used to increase mucosal hydration for any reason, including, but not limited to, treatment of dry eye disease, vaginal dryness, rhinosinusitis and dry mouth.
Dry eye disease is defined to include: keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren""s syndrome, ocular cicatrical pemphigoid, blepharitis, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamin), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink. The present invention may also be useful as an ophthalmic wash or irrigation solution in conscious individuals, during surgery (e.g. lasik, radial keratotomy, cataract removal) or to maintain comatose patients or those who cannot blink due to neuromuscular blockade, muscle or nerve damage, or loss of the eyelids. The compound uridine diphosphate (UDP) was found to be a potent stimulator of mucin secretion in tissue preparations containing goblet cells. Furthermore, an in vivo example of mucin secretion in accordance with the invention is conducted on an animal using impression cytology.
A method of stimulating cervical and vaginal secretions in a subject in need of such treatment is disclosed. The method of the present invention may be used to increase cervical and vaginal secretions for any reason, including, but not limited to, treatment of vaginal dryness. Vaginal dryness is associated with but not limited to menopause, childbirth, breastfeeding, chemotherapy or radiotherapy, diabetes mellitus, Sjogren""s syndrome, Ehlers-Danlos syndrome, systemic sclerosis and other systemic autoimmune diseases, hysterectomy, urogenital surgery, psychosomatic disorders, anxiety, psychosexual problems, and pharmacological drug-related side effects.
Furthermore, because of their general ability to rehydrate mucosal surfaces, the compounds of the present invention may also be useful in the treatment of rhinosinusitis and dry mouth. Additionally, it is postulated that the compounds of the present invention could be useful for the treatment of dry mouth.
The method of the present invention comprises administering a P2Y6 receptor agonist: uridine 5xe2x80x2-diphosphate, P1,P3-di(uridine-5xe2x80x2)triphosphate, cytidine 5xe2x80x2-diphosphate or adenosine 5xe2x80x2-diphosphate or analogs thereof, in an amount effective to stimulate mucosal hydration.
Another aspect of the present invention is the use of uridine 5xe2x80x2-diphosphate, P1, P3-di(uridine-5xe2x80x2)triphosphate, cytidine 5xe2x80x2-diphosphate or adenosine 5xe2x80x2-diphosphate or analogs thereof, for the manufacture of a medicament for carrying out a therapeutic method of treatment as given above.
The present invention also discloses pharmaceutical compositions comprising uridine 5xe2x80x2-diphosphate, P1,P3-di(uridine-5xe2x80x2)triphosphate, cytidine 5xe2x80x2-diphosphate or adenosine 5xe2x80x2-diphosphate or analogs thereof, with a pharmaceutical carrier therefor.
The present invention also discloses a method of detecting lung disease comprising administering uridine 5xe2x80x2-diphosphate, P1,P3-di(uridine-5xe2x80x2)triphosphate, cytidine 5xe2x80x2-diphosphate or adenosine 5xe2x80x2-diphosphate or analogs thereof, to at least one lung of an individual in order to facilitate the obtaining of a deep lung mucus, i.e., sputum sample, whereby the sputum sample is subjected to cytological, immunocytochemical, bacterial, or DNA analysis (e.g., via PCR) for detecting cellular abnormalities in the lung epithelium. The lung diseases detectable by this method include, but are not limited to lung cancer and tuberculosis. A preferred diphosphate compound for this diagnostic method is UDP (uridine 5xe2x80x2-diphosphate).